The interest of the pharmaceutical industry in combinatorial chemistry has driven increased research activity in solid-phase synthesis (Combinatorial Chemistry and Molecular Diversity in Drug Discovery Edited by Eric M. Gordon and James F. Kerwin, Jr. Wiley-Liss: New York. 1998. 516 pp. ISBN 0-47-15518-7.) to accomplish a wider range of chemistry. Similarly, new supported reagents and catalysts have emerged to facilitate the solution-phase synthesis and purification of compound library members. Crosslinked polystyrene-divinylbenzene (PS-DVB) matrices (Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149-2154) have been proven effective in solid-phase chemistry to produce peptides and small molecules, because of their relatively high functional group loading, reasonable swelling in selected solvents and mechanical stability. The hydrophobic polystyrene backbone has, however, poor compatibility with aqueous and polar solvents, potential reactivity under electrophilic chemical conditions, and is generally unsuitable for on-bead magic angle spinning (MAS) NMR analysis (Grotli, M.; Gotfredsen, C. H.; Rademann, J.; Buchardt, J.; Clark, A. J.; Duus, J. O.; Meldal, M. J. Comb. Chem. 2000, 2, 108-119). Several aqueous compatible resins have been prepared to overcome the shortcomings of the PS-DVB resins, including PEG-grafted crosslinked polystyrene resins, such as Tenta Gel (Rapp, W. In Combinatorial Peptide and Nonpeptide Libraries: A Handbook; Jung, G., Ed.; John Wiley & Sons: New York, 1998; pp 425-464) and ArgoGel (Labadie, J. W.; Deegan, T. L.; Gooding, O. W.; Heisler, K.; Newcomb, W. S.; Porco, J. A. Jr.; Tran, T. H.; Van Eikeren, P. Book of Abstracts, 212th ACS National Meeting, Orlando, Fla., Aug. 25-29 (1996)); as well as PEG cross-linked resins, such as PEGA (polyethylene glycol-dimethyacrylamide copolymer) (Renil, M.; Ferreras, M.; Delaisse, J. M.; Foged, N. T.; Meldal, M. J. Pept. Sci. 1998, 4, 195-210), POE-POP (polyoxyethylene-polyoxypropylene) (Renil, M.; Meldal, M. Tetrahedron Lett. 1996, 37, 6185-6188), Janda-Jel (Moss, J. A.; Dickerson, T. J.; Janda, K. D. Tetrahedron Lett. 2001, 43, 37-40), CLEAR (Cross-Linked Ethoxylate Acrylate Resins) (Kempe, M.; Barany, G. J. Am. Chem. Soc. 1996, 118, 7083-7093), and SPOCC (polyoxyethylene-polyoxetane) resins (Miranda, L. P.; Lubell, W. D.; Halkes, K. M.; Groth, T.; Grotli, M.; Rademann, J.; Gotfredsen, C. H.; Meldal, M. J. Comb. Chem. 2002, 4, 523-529). These resins typically possess poly(ethylene glycol) (PEG), which exhibits remarkable stability and good swelling in organic and aqueous media. Moreover, PEG-derived resins, such as Tenta Gel, PEGA, POE-POP, and SPOCC resins, all are generally suitable for MAS NMR analysis of resin-bound products (Grotli, M.; Goffredsen, C. H.; Rademann, J.; Buchardt, J.; Clark, A. J.; Duus, J. O.; Meldal, M. J. Comb. Chem. 2000, 2, 108-119).
The emergence of new strategies in combinatorial chemistry such as one-bead one-compound (Lam, K. S.; Salmon, S. E.; Hersh, E. M.; Hruby, V. J.; Kazmierski, W. M.; Knapp, R. J. Nature 1991, 354, 82-84) and on-bead screening of large compound libraries (Burger, M. T.; Bartlett, P. A. J. Am. Chem. Soc. 1977, 119, 12697-12698) requires new solid supports having high functional group loading and good swelling in a variety of solvents (Lam, K. S.; Lebl, M.; Krchnak, V. Chem. Rev. 1997, 97, 411-448). The functional group loading of most contemporary gel-type resins are normally between 0.2-0.4 mmol/g. Although dendrimer-based solid-phase supports have been prepared with higher functional group loading (Van Heerbeek, R.; Kamer, P. C. J.; Van Leeuwen, P. W. N. M.; Reek, J. N. H. Chem. Rev. 2002, 102(10), 3717-3756), their separation from the reaction media necessitates size exclusion chromatography. Moreover, the presence of amide and ester bonds within the dendrimer structure limits the chemistry, which can be performed on these supports (Lebreton, S.; Monaghan, S.; Bradley, M. Aldrichimica Acta 2001, 34, 75-83).
There was therefore a need for alternative resins that could have improved loading and swelling capacities as well as an enhanced stability.